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Molecular mechanism of corneal epithelial stratification and innervation

角膜上皮分层和神经支配的分子机制

基本信息

批准号：
10376207
负责人：
CHIA-YANG LIU
金额：
$ 6.36万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376207
关键词：
ARHGEF5 gene Adult Axon Basal Cell Behavior Biological Assay Biological Process Blindness Blinking Cell Line Cell Nucleus Cells Coculture Techniques Complex Cornea Corneal Diseases Cytomegalovirus Data Degenerative Disorder Development Disease Down-Regulation E-Cadherin Epithelial Epithelial Cells Esthesia Event Genes Histopathology Homeostasis Human Impairment In Vitro Keratopathy Knock-out Knowledge Lacrimation Lead Liquid substance Luciferases MAP Kinase Gene MAPK Signaling Pathway Pathway MEKs Maintenance Measures Mediating Mitogen-Activated Protein Kinases Molecular Molecular Target Monitor Morphogenesis Mouse Strains Mus Nerve Nerve Growth Factors Neurites Pathway interactions Play Proteins RAS genes Regulation Role Sensory Signal Pathway Signal Transduction Small Interfering RNA Squamous Epithelium Stratification Stratified Epithelium Stratified Squamous Epithelium Stratum Basale Structure of trigeminal ganglion Telomerase Thinness Tissues Transfection Transgenic Mice Trigeminal System Trigeminal nerve structure Ubiquitin Western Blotting base cell growth chromatin immunoprecipitation conditional knockout corneal epithelium density dosage experimental study extracellular gain of function ganglion cell knock-down migration multicatalytic endopeptidase complex mutant nerve supply new therapeutic target novel ocular surface overexpression pathogen plasmid DNA postnatal promoter response therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Corneal epithelium (CE) is composed of a single layer of basal cells and 4-5 cell layers of non- keratinized, stratified squamous epithelial cells to form an effective barrier against fluid loss and pathogen. CE is mainly innervated by trigeminal sensory afferents with extremely high density, which offers enormous sensitivity to the environmental insults for protecting otherwise deeper ocular tissues from damage by modulating the blink response and stimulating lacrimation. Any disruption of CE stratification and innervation can have deleterious effects on the integrity of the cornea and lead to neurotrophic keratopathy and corneal blindness. Little is known regarding the molecular and cellular mechanisms by which CE stratification and innervation is achieved during corneal morphogenesis and continuously sustained in the adulthood. In this proposal, we attempt to explore Shp2-mediated Ras–mitogen-activated protein kinase (Ras-MAPK) pathway which is extremely important for wide variety of cellular activities and behaviors, but it has not been studied in the CE stratification and innervation. We hypothesize that Shp2-mediated MAPK signaling controls CE stratification and innervation via regulating ∆Np63 expression. Three aims are proposed: Aim 1 is to elucidate the role of Shp2→Ras→Mek→∆Np63→E-cadherin signaling pathway in corneal epithelial stratification during and following development. Aim 2 is to elucidate the role of Shp2→Ras→Mek→∆Np63→NGF signaling axis of the CE on the CNV1 innervations during and following development. Aim 3 is to rescue otherwise impaired CE stratification and innervation by overexpression of ∆Np63α in Shp2cko mice. Completion of proposed objectives will delineate mechanistic event related to the Shp2-mediated Ras-MAPK pathway to fine-tune ∆Np63, which in turn regulate E-cadherin and NGF, to faciliate stratification and innervation of CE during development and in the maintenance of corneal homeostasis. This knowledge has great potential to lead to the discovery of pathway-based molecular target to treat corneal diseases such as neurotrophic keratopathy.

项目总结/摘要角膜上皮（CE）由单层基底细胞和4-5层非基底细胞组成，角化的、复层的鳞状上皮细胞，以形成有效的屏障防止液体流失，病原体CE主要由密度极高的三叉神经感觉传入神经支配，它提供了对环境损害的巨大敏感性，通过调节眨眼反应和刺激流泪来保护眼组织免受损伤。任何 CE分层和神经支配的破坏可能对脑组织的完整性产生有害影响。导致神经营养性角膜病和角膜盲。关于这一点，我们知之甚少。期间实现CE分层和神经支配的分子和细胞机制角膜形态发生并持续到成年期。在本提案中，我们试图探讨Shp 2介导的Ras丝裂原活化蛋白激酶（Ras-MAPK）通路，它对细胞的各种活动和行为极其重要，但尚未被研究 CE分层和神经支配。我们假设Shp 2介导的MAPK信号通路通过调节HCNp 63的表达来控制CE分层和神经支配。三个目标是提议的：目的：1.阐明Shp 2 →Ras→Mek→E-cadherin →E-cadherin信号通路在肝癌细胞凋亡中的作用。发育过程中和发育后的角膜上皮分层。目的2：阐明CE的Shp 2 →Ras→Mek→ JNp 63 →NGF信号轴在细胞凋亡中的作用。 CNV 1在发育期间和之后的神经支配。目的3是通过过度表达 Shp 2cko小鼠中的Np 63 α。完成拟定目标将描述与Shp 2介导的 Ras-MAPK途径微调JNP 63，进而调节E-cadherin和NGF，在角膜发育和维持过程中CE的分层和神经支配体内平衡。这些知识有很大的潜力，导致发现基于路径的分子靶点治疗角膜疾病，如神经营养性角膜病变。